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Journal of Diabetes Research
Volume 2013 (2013), Article ID 432659, 10 pages
Research Article

Pronerve Growth Factor Induces Angiogenesis via Activation of TrkA: Possible Role in Proliferative Diabetic Retinopathy

1Center for Pharmacy and Experimental Therapeutics, University of Georgia, 1120 15th Street HM-1200, Augusta, GA 30912, USA
2Culver Vision Discovery Institute, Georgia Reagents University, Augusta, GA 30912, USA
3Charlie Norwood VA Medical Center, Augusta, GA 30912, USA
4Department of Physiology, Georgia Reagents University, Augusta, Georgia 30912, USA
5Pharmacy Department, National Institutes of Health Clinical Center, Bethesda, MD 20892, USA

Received 30 April 2013; Revised 4 July 2013; Accepted 12 July 2013

Academic Editor: Mohamed Al-Shabrawey

Copyright © 2013 Sally L. Elshaer et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Proliferative diabetic retinopathy (PDR) is the leading cause of blindness in working age Americans. We demonstrated that diabetes disturbs the homeostasis of nerve growth factor (NGF) resulting in accumulation of its precursor proNGF. Increases in proNGF were positively correlated with progression of diabetic retinopathy, having the highest level in ocular fluids from PDR patients compared to nondiabetic patients. Here, we attempted to evaluate the contribution and the possible mechanism of proNGF to PDR. The angiogenic response of aqueous humor samples from PDR patients was examined in human retinal endothelial cells in the presence or absence of anti-proNGF antibody. Additional cultures were treated with mutant-proNGF in the presence of specific pharmacological inhibitors of TrkA and receptors. PDR-aqueous humor samples exerted significant angiogenic response including cell proliferation, migration, and alignment into tube-like structures. These effects were significantly reduced by anti-proNGF antibody but not by IgG. Treatment of retinal endothelial cells with mutant-proNGF activated phosphorylation of TrkA and p38MAPK; however, it did not alter expression. Inhibition of TrkA but not significantly reduced mutant-proNGF-induced cell proliferation, cell migration, and tube formation. Taken together, these results provide evidence that proNGF can contribute to PDR at least in part via activation of TrkA.